This invention pertains to the field of vasopressin antagonists. Vasopressin (also known as Antidiuretic Hormone, ADH) is a pituitary peptide hormone that is vital for the maintenance of proper water balance in animals and man. The antidiuretic effect of vasopressin concentrates the urine by increasing the reabsorption of water from the kidney filtrate. Thus, even under mild conditions of dehydration enhanced blood levels of vasopressin act to conserve water and control the proper osmolarity of the blood and extracellular fluids. Vasopressin also acts to contract vascular smooth muscle and may normally be involved in the maintenance of peripheral vascular resistance (McNieil, J.R., Can. J. Physiol Pharmacol 61: 1226-1235 (1983); Cowley, A.W., Quillen, E.W., and Skeleton, M.M., Federation Proceedings 42: 3170-3176 (1983)).
Recent studies have led to the development of relatively potent and specific antagonists of the antidiuretic or pressor effects of vasopressin (Sawyer, W.H., and Manning, M., Federation Proceedings 43: 87-90 (1984)). Because of the prominent actions of vasopressin on renal and cardiovascular function, vasopressin antagonists are useful in the treatment of several conditions including congestive heart failure, hypertension, and states of edema. The salt-sparing, `water diuretic` activity of vasopressin antagonists would be particularly useful in the treatment of hyponatremia which can arise from a variety of conditions (Zerbe, R., Stropes, L., Robertson, G., Ann. Rev. Med. 31: 315-327 (1980)). The currently known vasopressin antagonists are peptide analogues of vasopressin (Huffman, W.H., Ali, F.E., Bryan, W.M. et al. J. Med Chem 28: 1759-1760 (1985)) and are, therefore, likely to be rapidly metabolized in vivo and to have little, if any, oral activity (Lynn, R.K., Straub, K.M., Landvatter, S.W., and Garvey, C.T., Federation Proceedings 45: 205 (1986); Kinter, L.B., Mann, W.A., Woodward, P., DePalma, D. and Brennan, F., Federation Proceedings 45: 649 (1986)).
The non-peptide structure of the hapalindolinone compounds of the present invention would increase the likelihood of oral absorbtion and activity in comparison to known vasopressin antagonists of peptide structure (See Lynn et al. 1986; Kinten et al. 1986).
In addition, some hapalindole compounds having structures somewhat related to the compounds of the present invention have been reported as being useful as antibacterial and antifungal agents in EP Application 171,283 and Moore et al., J. Am. Chem. Soc. 106: 6456-57 (1984). There is, however, no suggestion that any of the fermentation products disclosed therein would be of use as vasopressin antagonists. Moreover, those compounds are structurally distinct from the compounds of the present invention.
It is, therefore, an object of the present invention to provide hapalindolinone compounds which are antagonists of vasopressin and are useful as pharmaceutical agents. It is also an object of the present invention to provide processes for producing these hapalindolinone compounds. It is a further object of the invention to provide a mixture of hapalindolinone compounds, called Hapalindolinone A and Hapalindolinone B (Formula IA and IB), produced by aerobic fermentation of a cyanobacterium of the genus Fischerella. A still further object is to provide cultures of the cyanobacterium of the genus Fischerella ATCC No. 53558 which are capable of producing hapalindolinone compounds and mixtures thereof.